According to the 2011 report of the World Health Organisation (WHO), infections caused by HIV-1 affected 34 million people worldwide in 2010, causing 2.7 million new cases and 1.8 million deaths.
In recent years, the use of antiretroviral therapy has resulted in a reduction of AIDS incidence and mortality. The current treatment of HIV-1 infection is based on combinations of three or four drugs that either inhibit the protease, reverse transcriptase or integrase of the virus, or block viral entry into the cell. However, these treatments do not eliminate the infection(1, 2). The appearance of resistance and the lack of an effective vaccine further underscore the need to search for new drugs aimed towards alternative targets. There is therefore an urgent need for new treatments effective at eliminating the infection caused by HIV-1.
RNA plays a central role in the functioning of living organisms(3), and many human, bacterial and viral RNA molecules have considerable therapeutic potential. Two strategies are currently being used to target these molecules. The first approach is based on the generation of antisense or RNAi molecules, aimed to base-pair with the intended RNA and in this way promote its degradation or block translation. The second strategy consists in the synthesis of small organic molecules designed to specifically recognize the cavities formed by tertiary RNA structures and interfere with their function(4, 5).
Functional and structured RNA motifs are not easily targeted by antisense agents and have the advantage of their high sequence and/or three-dimensional structure conservation. In the anti-infective field this is important, as it could result in a slower emergence of resistance to agents acting on them. Numerous natural products with antibiotic activity exert their action by binding to sites within bacterial ribosomal RNA. However, the development of new RNA-binding anti-infective agents has been hampered by the difficulties posed by these structures, which have limited physicochemical diversity and are often flexible(4-6). In order for this approach to be successful, it is essential to identify novel chemical scaffolds as well as new mechanisms of specific recognition of RNA structure.
The Rev Recognition Element (RRE) is a strongly conserved 350-nucleotide structure located in the env gene of human immunodeficiency virus type-1 (HIV-1) RNA. Within subdomain IIB of the RRE, the unusually widened major groove of a large GGCG:ACGGUA internal loop forms a high-affinity complex(7) with the arginine-rich α-helix of Rev (FIG. 1a), a virally-encoded 116-amino acid protein adopting a helix-turn-helix conformation(8, 9). This initial interaction between internal loop IIB of the RRE and the RNA-binding α-helix of Rev (hereafter designated Rev34-50) is essential for virus viability, as it triggers a cascade of events allowing the transport of unspliced or incompletely spliced viral RNA molecules to the cytoplasm of the infected cell in the late phase of the virus cycle. These events include the incorporation of additional Rev molecules to the complex(10), and the tethering of this RRE-Rev ribonucleoprotein to the Crm1 host export factor.
Evidence accumulated in recent years indicates that Rev has pleiotropic effects(11) in addition to RNA nuclear export, this protein has been shown to enhance translation and packaging(11, 12) and to control de nucleocytoplasmic shuttling of the HIV-1 integrase(13). Clearly, Rev represents a pivotal target for HIV-1 therapy. However, up to now the rational design of Rev-based inhibitors has remained an elusive goal, and none of the Rev- or RRE-based inhibitors evaluated so far have entered clinical use(14).